It is likely that cyclic GMP serves as a second messenger mediating the actions of hormones, transmitters, and modulators in the nervous system. However, the lack of simple, well-defined synaptic preparations in which to study the role of cyclic GMP has limited our ability to test this hypothesis. Recent work with the lobster neuromuscular junction suggests that this synaptic tissue is ideally suited for studies of hormonal modulation of cyclic GMP metabolism. Lobster neuromuscular preparations are physiologically well-defined, anatomically simple, relatively homogeneous, readily available in large quantities, and well-endowed with the enzymes involved in cyclic GMP metabolism. Furthermore, a set of molecules has been extracted from lobster secretory glands that elevate lobster muscle cyclic GMP levels by as much as 200-fold. Several (perhaps all) of these agents are peptides, and at least one of them (peptide G1) has been purified to homogeneity. Because these molecules are derived from neuroendocrine structures, and because they have such powerful effects on cyclic GMP metabolism, it seems likely that they represent a family of neurohormones that use the cyclic GMP as a second messenger. The recently- acquired amino acid sequence of peptide G1 supports this idea, by revealing strong homology between this peptide and a family of peptides that control energy metabolism and molting in other crustaceans (the CHH/MIH family). The purpose of the experiments in this proposal is to characterize the putative cyclic GMP-based neuroendocrine axis of the lobster: biochemical studies will investigate the degree to which peptide G1 (and the other cyclic GMP-promoting agents) can be released from the glands into the circulation, as expected of true neurohormones, and whether upon release they mimic the actions of the CHH/MIH family; cloning studies will attempt to define the peptide G1 receptor and its relationship to the guanylate cyclase effector mechanism in lobster muscle; and finally, physiological techniques will be used to investigate our preliminary observation that peptide G1 modulates excitation/contraction coupling at the lobster neuromuscular junction. In humans and other mammals a family of atrial natriuretic peptides regulates cyclic GMP levels in vascular smooth muscle, and thereby controls vascular tone and blood pressure. The properties of these vertebrate peptides are analogous in several striking ways to those of the lobster peptides described here. Thus, studies of cyclic GMP in the lobster may provide insight not only into the general mechanisms that regulate cyclic GMP metabolism, but may also enhance our understanding of human disorders that have been linked to the atrial natriuretic peptides. These include such muscle disorders as hypertension, coronary vasospasm, and atherosclerosis.